Ketamine-Assisted Treatment for Substance Use Disorders

Substance Use Disorders and the Search for Novel Treatments

Substance use disorders (SUDs) remain among the most prevalent and devastating conditions in global health. The World Health Organization estimates that over 35 million people worldwide suffer from drug use disorders, while alcohol use disorder affects approximately 400 million individuals. In the United States, the opioid crisis has claimed over one million lives since 1999, and alcohol-attributable deaths exceed 140,000 per year.

Despite decades of research, the pharmacological treatment options for SUDs remain limited. Approved medications for alcohol use disorder — disulfiram, naltrexone, and acamprosate — have modest efficacy, and relapse rates remain high across all substance categories. The recognition that ketamine may have therapeutic potential in addiction treatment has opened a novel line of clinical investigation, one that intersects neuropharmacology, psychotherapy, and the emerging field of psychedelic-assisted treatment. To understand the underlying science, see our guide on how ketamine works in the brain.

Historical Context

The investigation of ketamine for addiction is not entirely new. In the 1980s and 1990s, Russian psychiatrist Evgeny Krupitsky pioneered the use of ketamine-assisted psychotherapy (KAP) for alcohol and heroin dependence. His work demonstrated that ketamine sessions combined with psychotherapy produced significantly higher abstinence rates compared to conventional treatment alone — findings that, while initially met with skepticism in Western psychiatry, have been increasingly validated by modern clinical trials.

Krupitsky's approach was distinctive in that it utilized the psychedelic-like properties of ketamine — the altered states of consciousness, ego dissolution, and mystical-type experiences that can occur at sub-anesthetic to near-anesthetic doses — as therapeutic tools rather than merely side effects. This conceptual framework aligns with the broader psychedelic-assisted therapy paradigm that has gained scientific credibility in recent years.

Clinical Evidence by Substance Type

Alcohol Use Disorder

The strongest evidence for ketamine in addiction treatment comes from alcohol use disorder (AUD) research. A landmark 2022 randomized controlled trial published in the American Journal of Psychiatry — the KARE trial — enrolled 96 patients with severe AUD and compared ketamine-assisted psychotherapy to placebo-assisted psychotherapy.

Key findings from the KARE trial:

• Patients in the ketamine group had significantly more days abstinent from alcohol over the six-month follow-up period (162 days vs. 116 days in the placebo group)
• 86% of the ketamine group was completely abstinent at the end of the trial, compared to 62% in the placebo group
• The ketamine sessions were well-tolerated, with no serious adverse events

Additional studies have explored IV ketamine infusions (without the structured psychotherapy component) for AUD, with mixed but generally positive results. These findings suggest that while ketamine alone may have some anti-craving effects, the combination with psychotherapy appears to produce more robust and sustained outcomes.

Opioid Use Disorder

Research into ketamine for opioid use disorder is more limited but emerging. A 2019 pilot study examined repeated ketamine infusions in patients with opioid use disorder who were receiving buprenorphine maintenance therapy. Participants showed reduced craving and improved mood, though the small sample size limited the conclusions that could be drawn.

The relationship between ketamine and opioid systems is complex. Ketamine interacts with opioid receptors in addition to NMDA receptors, and some researchers have hypothesized that this opioid activity could be either beneficial (by reducing craving) or problematic (by potentially reinforcing addictive circuitry) in opioid-dependent populations. This uncertainty underscores the need for careful, controlled research.

Cocaine Use Disorder

A notable study by Dakwar and colleagues at Columbia University examined ketamine for cocaine dependence. In a 2019 randomized controlled trial, individuals with cocaine use disorder who received a single ketamine infusion during a period of abstinence showed significantly reduced cocaine use over the subsequent two-week period compared to those receiving a control infusion. Additionally, ketamine-treated participants demonstrated reduced craving and greater motivation to quit.

A follow-up study combining ketamine with mindfulness-based relapse prevention therapy showed even more pronounced effects, with 48% of the ketamine-plus-therapy group achieving end-of-study abstinence compared to 11% of the control group. These results suggest that the synergy between ketamine's neuroplastic effects and psychotherapeutic intervention may be particularly powerful in cocaine addiction.

Tobacco and Other Substances

Preliminary investigations have explored ketamine for nicotine dependence and cannabis use disorder, though the evidence base for these applications remains thin. The theoretical rationale — that ketamine-enhanced neuroplasticity could facilitate the unlearning of addictive behaviors — applies broadly across substance types, but clinical validation is needed for each specific indication.

Mechanisms of Action in Addiction

Disruption of Reward-Related Memory

Addiction involves the formation of powerful, maladaptive memories linking substance use with reward, environmental cues, and emotional states. These memories drive craving and relapse even after prolonged abstinence. Ketamine may disrupt addiction-related memory through several mechanisms:

• NMDA receptor blockade interferes with the reconsolidation of drug-associated memories, potentially weakening their grip on behavior
• Ketamine-induced neuroplasticity may facilitate the formation of new, adaptive associations that compete with drug-related memories
• The dissociative experience itself may provide a novel cognitive perspective that helps reframe the relationship with substances

Enhancement of Neuroplasticity

The rapid synaptogenic effects of ketamine — mediated through BDNF release, mTOR pathway activation, and AMPA receptor stimulation — may create a window of enhanced neural plasticity during which therapeutic learning is facilitated. This window is thought to be critical for the efficacy of ketamine-assisted psychotherapy, as new patterns of thinking and behavior established during this period may be more effectively consolidated into long-term neural circuits.

Glutamate Normalization

Chronic substance use is associated with significant glutamatergic dysregulation, including reduced glutamate clearance in the nucleus accumbens (a key reward center) and altered NMDA and AMPA receptor expression. Ketamine's modulation of the glutamate system may help normalize these abnormalities, restoring healthier patterns of neurotransmission in reward and decision-making circuits.

Psychological and Existential Mechanisms

At doses that produce significant dissociative or psychedelic-like experiences, ketamine can facilitate profound psychological experiences — including feelings of ego dissolution, interconnectedness, and perspective shifts on life and mortality. In the context of structured psychotherapy, these experiences may catalyze motivation for change, self-compassion, and a renewed sense of meaning and purpose. Research has shown that the intensity of the mystical-type experience during ketamine sessions correlates with treatment outcome in addiction studies.

The Ketamine-Assisted Psychotherapy (KAP) Model

Treatment Structure

Ketamine-assisted psychotherapy for SUDs typically follows a structured protocol:

1. Preparation sessions — Psychotherapy sessions before ketamine administration to establish therapeutic rapport, set treatment intentions, and develop a framework for understanding the ketamine experience
2. Ketamine sessions — Administration of ketamine (typically IV or IM) in a supportive therapeutic environment, with trained therapists present throughout
3. Integration sessions — Psychotherapy sessions following ketamine administration to process the experience, extract meaningful insights, and translate them into behavioral change

Dosing Considerations

The dosing approach in KAP for addiction often differs from that used in depression treatment. Some protocols employ higher doses (0.5-0.8 mg/kg IV or 3-4 mg/kg IM) to produce more psychedelic-like experiences, based on the theory that the depth of the altered state contributes to therapeutic outcome. Other protocols use standard antidepressant doses (0.5 mg/kg IV). The optimal dosing strategy remains an active area of investigation.

Ethical and Safety Considerations

The Paradox of Treating Addiction With a Potentially Addictive Substance

The most obvious concern with using ketamine to treat addiction is that ketamine itself has abuse potential. As a Schedule III controlled substance, ketamine can produce pleasurable effects, and recreational misuse is well-documented. However, several factors mitigate this concern in clinical settings:

• Ketamine is administered in controlled medical environments with professional supervision
• Treatment protocols typically involve a limited number of sessions rather than ongoing self-administration
• Research data have not shown increased rates of ketamine misuse among patients treated for SUDs
• The therapeutic model emphasizes psychological insight rather than hedonic effects

Careful patient screening, structured treatment protocols, and ongoing monitoring are essential to minimize abuse risk.

Patient Selection

Screening for ketamine-assisted addiction treatment should include assessment of:

• Severity and duration of the substance use disorder
• History of treatment attempts and responses
• Co-occurring psychiatric conditions, particularly psychotic disorders
• Cardiovascular health and medication interactions
• Motivation for treatment and willingness to engage in psychotherapy
• Specific assessment of any history of ketamine misuse

Future Directions

The field of ketamine-assisted addiction treatment is advancing rapidly. Key areas of ongoing research include:

• Larger, multi-site randomized controlled trials for AUD, opioid use disorder, and cocaine use disorder
• Optimization of dosing protocols and psychotherapy frameworks
• Identification of biomarkers predicting treatment response
• Comparison of ketamine with other psychedelic-assisted approaches (psilocybin, MDMA) for addiction
• Investigation of at-home ketamine protocols for addiction maintenance therapy
• Long-term follow-up studies assessing durability of treatment effects

The convergence of neuroplasticity-based pharmacology and structured psychotherapy in ketamine-assisted treatment represents a paradigm shift in addiction medicine — one that holds significant promise for a patient population with limited treatment options.

Note: This article is for educational purposes only and does not constitute medical advice. Ketamine-assisted therapy for substance use disorders is an emerging treatment area, and individuals should consult qualified healthcare providers to discuss available evidence and treatment options.

References

• NIDA: National Institute on Drug Abuse — Federal research resource on substance use, addiction neuroscience, and treatment development
• SAMHSA: Substance Abuse and Mental Health Services Administration — Federal agency providing information on substance use treatment and recovery services
• StatPearls: Ketamine — Clinical reference covering ketamine pharmacology and abuse potential considerations
• NIMH: Depression — National Institute of Mental Health information on comorbid depression and substance use disorders